Trifluoromethyl group plays a pivotal role in many industrial sectors such as pharmaceuticals, agrochemicals, dyes, polymers and material chemistry. It is well-known that introduction of fluorine in pharmaceutical targets increases the possibility of such compounds to act as “lead compounds” by almost tenfold (Taj, S. A. S. Chemical Industry Digest, 2008, 21, 92-98). Trifluoromethyl group increases the lipophilicity of biologically active compounds so that they can be absorbed by the body easily and can reach specific binding sites more effectively (Mueller, K., Faeh, C. and Diederich, F. Science 2007, 317, 1881-1886; Cho, E. J., Senecal, T. D., Kinzel, T., Zhang, Y., Watson, D. A. and Buchwald, S. L. Science 2010, 328, 1679-1681).
Consequently, the key challenge in the field is to develop safer, cheaper, environmentally friendly and more efficient trifluoromethylation methods. Nucleophilic trifluoromethylation is more attractive and well-studied to synthesize variety of trifluoromethylated building blocks. The most common reagent of choice for nucleophilic trifluoromethylation is trifluoromethyltrimethylsilane (TMS-CF3), 1, also known as Ruppert-Prakash reagent (Ruppert, I., Schlich, K. and Volbach, W. Tetrahedron Lett., 1984, 25, 2195-2198; Ramaiah, P., Krishnamurti, R. and Prakash, G. K. S. Org. Synth., 1995, 72, 232-40). Trifluoromethyltrimethylsilane, 1, acts as a “trifluoromethide” equivalent in nucleophilic trifluoromethylation reactions (Prakash, G. K. S., Krishnamurti, R. and Olah, G. A. J. Am. Chem. Soc., 1989, 111, 393-395). Variety of methods have already been developed using this reagent to carry out nucleophilic trifluoromethylation of aldehydes, ketones, esters, imines, and many other electrophiles (both achiral and prochiral). (Prakash, G. K. S. and Yudin, A. K. Chem. Rev., 1997, 97, 757-786; Singh, R. P. and Shreeve, J. M. Tetrahedron, 2000, 56, 7613-7632; Prakash, G. K. S. and Hu, J. ACS Symp. Ser., 2005, 911, 16-56; Mizuta, S., Shibata, N., Sato, T., Fujimoto, H., Nakamura, S. and Toni, T. Synlett, 2006, 267-270; Kawai, H., Kusuda, A., Mizuta, S., Nakamura, S., Funahashi, Y., Masuda, H. and Shibata, N. J. Fluorine Chem., 2009, 130, 762-765). TMS-CF3 (1) is commercially available and it is a very easy to handle liquid (bp=54-55° C.), both on industrial and laboratory scale.
Synthesis of TMS-CF3 is also well studied and there are several methods, which are reported earlier (Ruppert, I., Schlich, K. and Volbach, W. Tetrahedron Lett., 1984, 25, 2195-2198; Ramaiah, P., Krishnamurti, R. and Prakash, G. K. S. Org. Synth., 1995, 72, 232-40; Beckers, H., Buerger, H., Bursch, P. and Ruppert, I. J. Organomet. Chem., 1986, 316, 41-50; Pawelke, G. J. Fluorine Chem., 1989, 42, 429-33; Deffieux, D., Bordeau, M., Biran, C. and Dunogues, J. Organometallics, 1994, 13, 2415-2422; Grobe, J. and Hegge, J. Synlett, 1995, 641-2; Prakash, G. K. S., Yudin, A. K., Deffieux, D. and Olah, G. A. Synlett, 1996, 151-3; Martynov, B. I. and Stepanov, A. A. J. Fluorine Chem., 1997, 85, 127-128; Prakash, G. K. S., Hu, J. and Olah, G. A. J. Org. Chem., 2003, 68, 4457-4463; Prakash, G. K. S., Hu, J. and Olah, G. A. 2004, US 2004/0230079 (A1), 33 pp; Prakash, G. K. S., Hu, J., Olah, G. A. and Wang, Y. 2005, US 2006/0052643 (A1), 28 pp). This reagent can be prepared by electrochemical procedures (Prakash, G. K. S., Deffieux, D., Yudin, A. K. and Olah, G. A. Synlett, 1994, 1057-8). In most of these methods the actual trifluoromethyl starting components include CF3I, (Pawelke, G. J. Fluorine Chem., 1989, 42, 429-33) CF3Br (Ruppert, I., Schlich, K. and Volbach, W. Tetrahedron Lett., 1984, 25, 2195-2198; Ramaiah, P., Krishnamurti, R. and Prakash, G. K. S. Org. Synth., 1995, 72, 232-40), etc. Both CF3Br and CF3I are known ozone depleting gases and moreover their use is being regulated (Montreal protocol), which has resulted in slowing down the development of the synthesis of TMS-CF3 on a large industrial scale. Intuitively, the simplest and rather atom economical source of the CF3 moiety would be trifluoromethane (CF3H). A multi-step synthesis of TMS-CF3 (1) using trifluoromethane (via trifluoromethyl sulfide, sulfoxides and sulfones) and chlorosilanes using Mg mediated trifluoromethylation method has already been reported. (Prakash, G. K. S., Hu, J. and Olah, G. A. J. Org. Chem., 2003, 68, 4457-4463; Prakash, G. K. S., Hu, J. and Olah, G. A. 2004, US 2004/0230079 (A1), 33 pp). However, a direct trifluoromethylation of chlorosilanes with trifluoromethane to synthesize 1 and other higher trifluoromethylated silanes is still elusive. This is mainly due to the inherent and very well documented instability of trifluoromethyl anion even at very low temperatures. Trifluoromethyl anion (CF3−), due to its concentrated negative charge around the carbon atom, is known to decompose rapidly into fluoride ion (F−) and an electron deficient singlet carbene, difluorocarbene, (:CF2) (Prakash, G. K. S. and Mandal, M. J. Fluorine Chem., 2001, 112, 123-131; Large, S., Rogues, N. and Langlois, B. R. J. Org. Chem., 2000, 65, 8848-8856; Billard, T., Bruns, S. and Langlois, B. R. Org. Lett., 2000, 2, 2101-2103; Billard, T., Langlois, B. R. and Blond, G. Eur. J. Org. Chem., 2001, 1467-1471; Russell, J. and Rogues, N. Tetrahedron, 1998, 54, 13771-13782; Langlois, B. R. and Billard, T. Synthesis, 2003, 185-194).
Trifluoromethane, a by-product of the Teflon industry, is produced in large amounts on an industrial scale. Its efficient production has already been reported via fluorination of methane with hydrogen fluoride and chlorine. (Webster, J. L. and Lerou, J. J. 1995, U.S. Pat. No. 5,446,218 (A) 8 pp Cont-in-part of U.S. Ser. No. 51,917, abandoned). It is a non toxic, non ozone-depleting gas, but has a powerful greenhouse effect, which rules out its use as a refrigerant. Use of trifluoromethane gas in synthetic organic chemistry is a great challenge for a variety of reasons such as its low boiling point (bp=−83° C.), relatively high pKa (25-28), and low reactivity (being a relatively weak acid). On the other hand, this also can be considered as an interesting opportunity to develop synthetically useful methods by which one could convert an unused and accumulating byproduct, which is of environmental concern (because of green-house warming potential) into practical interests.
In 1991, Shono and others showed that an electrochemically generated base using 2-pyrrolidone can be used to deprotonate trifluoromethane, which generates in situ trifluoromethyl anion equivalent which then trifluoromethylates aldehydes and ketones (Shono, T., Ishifune, M., Okada, T. and Kashimura, S. J. Org. Chem., 1991, 56, 2-4). Troupel and others also showed that a strong base generated by cathodic reduction of iodobenzene can deprotonate trifluoromethane and consequently can then add to aldehydes (Barhdadi, R., Troupel, M. and Perichon, J. Chem. Commun., 1998, 1251-1252). Later on, two research groups have carried out extensive work where trifluoromethane is used as a source of trifluoromethyl anion. Normant et al. published their work on trifluoromethylation of aldehydes by deprotonation of trifluoromethane using Dimsyl-K (base generated from DMSO) in DMF (Folléas, B., Marek, I., Normant, J.-F. and Jalmes, L. S. Tetrahedron Lett., 1998, 39, 2973-2976). It was postulated that an adduct of CF3− and DMF (hemiaminolate) acts as a reservoir of CF3− anion and it was the true trifluoromethyl transfer intermediate. Subsequently, Langlois, Rogues and others reported trifluoromethylation of aldehydes, non-enolizable ketones and disulfides with an excess of CF3H and strong bases in DMF as a solvent, all of these are included herein as a reference (Large, S., Rogues, N. and Langlois, B. R. J. Org. Chem., 2000, 65, 8848-8856; Rogues, N., Russell, J., Langlois, B., Saint-Jalmes, L., Large, S. and et, a. 1998, WO 98/22435 (A1), 105 pp; Rogues, N. and Russell, J. 1997, U.S. Pat. No. 6,355,849 (B1), 32 pp; Langlois, B., Billard, T. and Garlyauskayte, R. 2003, FR 2827285 (A1), 22 pp). However, this method is limited to the use of dimethylformamide (or any amide containing reagent) to trap the trifluoromethyl anion in a hemi-aminolate and in absence of which the reaction does not seem to work well. In addition, in all of the reported reactions excess of trifluoromethane was used to achieve the desired trifluoromethylation reactions.
Based on the above, it is quite clear that there is a need to develop newer more direct trifluoromethylation methods, which use trifluoromethane as a direct trifluoromethylating source. These methods should be synthetically useful and versatile; practical, unrestricted (without any prerequisite solvent trap such as DMF) in terms of solvents used for the reaction and without the use of excess of trifluoromethane gas. Most beneficial would be a single step reaction between trifluoromethyl anion (CF3−), generated in situ from trifluoromethane and a given electrophile under suitable reaction conditions. Such methods would not only solve the environmental problem, which we face in future due to excess accumulation of this gas but would also provide practical synthetic applications.